Parathyroid hormone-related protein (PTHrP) was discovered through its role in causing humoral hypercalcemia of malignancy (HHM). It is now clear that PTHrP not only is the cause of HHM, but also plays critical roles in skeletal development. Moreover, PTHrP is produced by almost every tissue in the body and acts as a regulator of: a) transepithelial calcium transport; b) smooth muscle tone; and, c) cellular growth, differentiation, apoptosis and organogenesis. The original version of this proposal focused on identifying the function of PTHrP in the pancreatic beta cell. To approach this question, we developed transgenic mice which overexpress PTHrP within the pancreatic beta cell using the rat insulin-II promoter (RIP). The studies performed to date indicate that RIP-PTHrP mice develop striking islet hyperplasia which results in hyperinsulinemia, and hypoglycemia. This is the only transgenic model of islet hyperplasia and hypoglycemia The mechanisms responsible for the increase in islet mass and function, however, are unclear: there are no changes in the rate of apoptosis nor of proliferation in RIP-PTHrP islets. In addition, while these studies demonstrate the consequences of targeted overexpression of PTHrP within the islet, they do not reveal whether PTHrP plays a normal role in the regulation of islet mass. The current proposal represents a natural extension of these studies. It has two Aims: 1. To Further Define the Mechanism by which PTHrP Increases Islet Mass. 2. To Determine Whether PTHrP Plays a Role in Normal Islet Physiology. These studies should more clearly define the role of PTHrP within the islet and should help to clarify whether PTHrP might prove of value in the treatment of diabetes. Most importantly, these studies should broaden the understanding of the mechanisms of action of PTHrP in the large range of normal tissues (parathyroid glands, the epidermis, the mammary gland, and the skeleton) which produce this ubiquitous paracrine/autocrine/intracrine factor.